No description available.

2.9 mM etoposide in CDCl3 and CDCl3/(D20) were studied at 300 and 500 MHz NMR. One dimensional (1D) NMR spectra and truncated lD Nuclear Overhauser Effect (NOE) buildup experiments were used to find direct information on the structure of etoposide. Results showed that the E-ring rotates freely about the C1’-C4 bond and is oriented to the side where H2’, H4 project. The C and D rings have a "trans" junction at C2-C3 bond. The ethylidene-glucopyranosyl group approaches the D ring allowing close interaction between H1” and H8. Water spin - transfer experiments were done to determine the interaction between water and the etoposide molecule. Chemical shifts of 2" -OH, 3" -OH were found to be affected remarkably by changes in water concentration due to the hydration of these hydroxide groups by H-bonding with water. Relaxation experiments were done to measure the longitudinal relaxation time and the whole molecular tumbling speed in solution (τc is 0.6 ns at 500 MHz). Higher than average T1 differences between wet sample and dry samples were observed for 4'-0H, H8, H3, H5, H2”. It is suggested that some water residues are associated with these nuclei. The 4'-0H is obviously hydrated by water via H-bonding (as above). Two dimensional NOE spectroscopy (NOESY & ROESY) experiments were done to give the distance constraints for running molecular dynamics (MD). Computer simulation and modeling were carried out to build up the molecule with restraint molecular dynamics (rMD) calculations by Amber 4.1. Temperature annealing, time-averaged distance restraint and water-solute interactions were applied to in these simulations. Several water bridges were found by calculation to correspond to the interactions seen to effect hydrogens by NMR. The hydration of etoposide also accounts for the slower relaxation rates in partially aqueous CDCl3 solution.

Aterosclerose é uma doença inflamatória e proliferativa que tem início quando fatores de risco alteram o endotélio vascular. Células inflamatórias e vasculares liberam citocinas e fatores de crescimento que estimulam a proliferação e migração das células de músculo liso e a síntese de componentes da matriz extracelular. A nanoemulsão lipídica LDE se concentra em regiões onde a proliferação celular e a inflamação são maiores, tornando-se um veículo para fármacos. O etoposide, fármaco antiproliferativo, ainda não foi explorado no tratamento da aterosclerose. O paclitaxel recobre stents utilizados em angioplastia para evitar a reestenose. A associação do LDE-etoposide ao LDE-paclitaxel aumentaria o efeito antiproliferativo dos fármacos isolados, por agirem em diferentes fases do ciclo celular. Este estudo tem por objetivos avaliar a eficácia do tratamento com LDE-etoposide e com a combinação LDE-etoposide/LDE-paclitaxel da aterosclerose induzida por dieta rica em colesterol em coelhos; comparar a eficácia dos tratamentos; no grupo de tratamento mais eficaz e no grupo Controle, avalia a expressão protéica de receptores de lipoproteínas, citocinas, MMP9 e marcadores de proliferação celular. Para tanto, 27 coelhos receberam dieta rica em colesterol por 8 semanas. Depois de 4 semanas, foram divididos em 3 grupos: grupo Controle, que recebeu 6 mL de solução salina intravenosa; LDE-etoposide, que recebeu dose de 6mg/kg; e grupo Combinação, que recebeu LDE-etoposide/LDE-paclitaxel nas doses de 6mg/kg e 4mg/kg, respectivamente. Os tratamentos foram administrados uma vez por semana durante 4 semanas. Foram avaliados perfil lipídico, hematológico, ponderal e o consumo de ração. Após a eutanásia, as lesões ateroscleróticas macroscópicas foram medidas. Depois, o arco aórtico foi analisado por morfometria e por imunohistoquímica. Foi observado que não houve diferença no perfil ponderal e no consumo de ração entre os grupos de estudo. No perfil lipídico, ao final do estudo, as concentrações de colesterol total e de triglicérides aumentaram em todos os grupos. O perfil hematológico mostrou redução do número de hemácias nos grupos de tratamento ao final do estudo. Em comparação com o grupo Controle, os animais tratados com LDE-etoposide apresentaram lesões ateroscleróticas 11 vezes menores e o grupo Combinação, apresentou lesões 3 vezes menores. Na análise morfométrica, a área total e a espessura da aorta foram menores no grupo LDE-etoposide quando comparado com os outros dois grupos. O grupo tratado com LDE-etoposide apresentou presença de macrófagos e de células de músculo liso menor que os grupos Controle e Combinação. Como o tratamento com LDE-etoposide apresentou uma maior eficácia, a avaliação dos outros fatores foi feita apenas neste grupo e no grupo Controle para comparação. O grupo LDE-etoposide apresentou menor expressão protéica dos receptores de lipoproteínas, das citocinas inflamatórias, da MMP9 e dos marcadores de proliferação celular topoisomerase II e tubulina. As avaliações mostraram que o tratamento com LDE-etoposide foi mais eficaz no tratamento das lesões ateroscleróticas induzidas em coelhos do que a combinação entre LDE-etoposide/LDE-paclitaxel / Atherosclerosis is an inflammatory and proliferative disease that is triggered by risk factors damaging vascular endothelium. Inflammatory and vascular cells release cytokines and growth factors, promoting the proliferation and migration of smooth muscle cells and extracellular matrix elements synthesis. LDE, an artificial nanoemulsion, concentrates in areas of greater proliferation and inflammation rates and can be used as a vehicle to direct drugs to those cells. Etoposide, an antiproliferative drug, have not been studied in atherosclerosis treatment. Paclitaxel is used in drug-eluting stents to avoid restenosis. The association of LDE-etoposide and LDE-paclitaxel would enhance the antiproliferativo effect of the isolated drugs, due to act in different cell cycle phase. The aim of this study was to evaluate the effectiveness of the treatment with LDE-etoposide and with LDE-etoposide/LDE-paclitaxel of atherosclerosis induced by a cholesterol-rich diet in rabbits; compare the effectiveness of these treatments; in the most effective treatment group and in Control group, evaluate the protein expression of lipoprotein receptors, cytokines, MMP9 and cell proliferation markers. To do so, 3 groups of 9 rabbits were fed a cholesterol-rich diet during 8 weeks then the animals were separated in 3 groups: Control, intravenously injected with 6mL of saline solution; LDE-etoposide, injected with a dose 6mg/kg; and Combination, injected with LDE-etoposide/LDE-paclitaxel in a dose of 6mg/kg and 4mg/kg, respectively. Treatments were administered once a week during 4 weeks. Lipids, blood cell count, weight and food intake were evaluated. The animals were sacrificed and the macroscopic atherosclerotic lesions were measured. Later, the aortic arch was analyzed by microscopic morphometry and by immunohistochemistry. It was seen that there was no difference in food intake and weight between study groups. Total cholesterol and triglycerides concentration increased in all groups. Blood cell count showed reduction of red blood cell in treatment groups at the end of the study. Animals treated with LDE-etoposide showed 11-fold less lesions and Combination group showed 3-fold less lesions than Control group. By morphometric analysis, total area and thickness of aorta were smaller in LDE-etoposide group than the other groups. LDE-etoposide group showed less macrophages and smooth muscle cells than Control and Combination groups. As treatment with LDE-etoposide showed a better efficacy, evaluation of other factor were performed only in LDE-etoposide and Control group, to perform a comparison. LDE-etoposide showed less protein expression of lipoprotein receptors, cytokines, MMP9, and of cell proliferation markers topoisomerase II and tubulina. The analysis showed that LDE-etoposide treatment was more effective in treating atherosclerotic-induced lesions in rabbits than the combination between LDE-etoposide/LDE-paclitaxel

Aterosclerose é uma doença inflamatória e proliferativa que tem início quando fatores de risco alteram o endotélio vascular. Células inflamatórias e vasculares liberam citocinas e fatores de crescimento que estimulam a proliferação e migração das células de músculo liso e a síntese de componentes da matriz extracelular. A nanoemulsão lipídica LDE se concentra em regiões onde a proliferação celular e a inflamação são maiores, tornando-se um veículo para fármacos. O etoposide, fármaco antiproliferativo, ainda não foi explorado no tratamento da aterosclerose. O paclitaxel recobre stents utilizados em angioplastia para evitar a reestenose. A associação do LDE-etoposide ao LDE-paclitaxel aumentaria o efeito antiproliferativo dos fármacos isolados, por agirem em diferentes fases do ciclo celular. Este estudo tem por objetivos avaliar a eficácia do tratamento com LDE-etoposide e com a combinação LDE-etoposide/LDE-paclitaxel da aterosclerose induzida por dieta rica em colesterol em coelhos; comparar a eficácia dos tratamentos; no grupo de tratamento mais eficaz e no grupo Controle, avalia a expressão protéica de receptores de lipoproteínas, citocinas, MMP9 e marcadores de proliferação celular. Para tanto, 27 coelhos receberam dieta rica em colesterol por 8 semanas. Depois de 4 semanas, foram divididos em 3 grupos: grupo Controle, que recebeu 6 mL de solução salina intravenosa; LDE-etoposide, que recebeu dose de 6mg/kg; e grupo Combinação, que recebeu LDE-etoposide/LDE-paclitaxel nas doses de 6mg/kg e 4mg/kg, respectivamente. Os tratamentos foram administrados uma vez por semana durante 4 semanas. Foram avaliados perfil lipídico, hematológico, ponderal e o consumo de ração. Após a eutanásia, as lesões ateroscleróticas macroscópicas foram medidas. Depois, o arco aórtico foi analisado por morfometria e por imunohistoquímica. Foi observado que não houve diferença no perfil ponderal e no consumo de ração entre os grupos de estudo. No perfil lipídico, ao final do estudo, as concentrações de colesterol total e de triglicérides aumentaram em todos os grupos. O perfil hematológico mostrou redução do número de hemácias nos grupos de tratamento ao final do estudo. Em comparação com o grupo Controle, os animais tratados com LDE-etoposide apresentaram lesões ateroscleróticas 11 vezes menores e o grupo Combinação, apresentou lesões 3 vezes menores. Na análise morfométrica, a área total e a espessura da aorta foram menores no grupo LDE-etoposide quando comparado com os outros dois grupos. O grupo tratado com LDE-etoposide apresentou presença de macrófagos e de células de músculo liso menor que os grupos Controle e Combinação. Como o tratamento com LDE-etoposide apresentou uma maior eficácia, a avaliação dos outros fatores foi feita apenas neste grupo e no grupo Controle para comparação. O grupo LDE-etoposide apresentou menor expressão protéica dos receptores de lipoproteínas, das citocinas inflamatórias, da MMP9 e dos marcadores de proliferação celular topoisomerase II e tubulina. As avaliações mostraram que o tratamento com LDE-etoposide foi mais eficaz no tratamento das lesões ateroscleróticas induzidas em coelhos do que a combinação entre LDE-etoposide/LDE-paclitaxel / Atherosclerosis is an inflammatory and proliferative disease that is triggered by risk factors damaging vascular endothelium. Inflammatory and vascular cells release cytokines and growth factors, promoting the proliferation and migration of smooth muscle cells and extracellular matrix elements synthesis. LDE, an artificial nanoemulsion, concentrates in areas of greater proliferation and inflammation rates and can be used as a vehicle to direct drugs to those cells. Etoposide, an antiproliferative drug, have not been studied in atherosclerosis treatment. Paclitaxel is used in drug-eluting stents to avoid restenosis. The association of LDE-etoposide and LDE-paclitaxel would enhance the antiproliferativo effect of the isolated drugs, due to act in different cell cycle phase. The aim of this study was to evaluate the effectiveness of the treatment with LDE-etoposide and with LDE-etoposide/LDE-paclitaxel of atherosclerosis induced by a cholesterol-rich diet in rabbits; compare the effectiveness of these treatments; in the most effective treatment group and in Control group, evaluate the protein expression of lipoprotein receptors, cytokines, MMP9 and cell proliferation markers. To do so, 3 groups of 9 rabbits were fed a cholesterol-rich diet during 8 weeks then the animals were separated in 3 groups: Control, intravenously injected with 6mL of saline solution; LDE-etoposide, injected with a dose 6mg/kg; and Combination, injected with LDE-etoposide/LDE-paclitaxel in a dose of 6mg/kg and 4mg/kg, respectively. Treatments were administered once a week during 4 weeks. Lipids, blood cell count, weight and food intake were evaluated. The animals were sacrificed and the macroscopic atherosclerotic lesions were measured. Later, the aortic arch was analyzed by microscopic morphometry and by immunohistochemistry. It was seen that there was no difference in food intake and weight between study groups. Total cholesterol and triglycerides concentration increased in all groups. Blood cell count showed reduction of red blood cell in treatment groups at the end of the study. Animals treated with LDE-etoposide showed 11-fold less lesions and Combination group showed 3-fold less lesions than Control group. By morphometric analysis, total area and thickness of aorta were smaller in LDE-etoposide group than the other groups. LDE-etoposide group showed less macrophages and smooth muscle cells than Control and Combination groups. As treatment with LDE-etoposide showed a better efficacy, evaluation of other factor were performed only in LDE-etoposide and Control group, to perform a comparison. LDE-etoposide showed less protein expression of lipoprotein receptors, cytokines, MMP9, and of cell proliferation markers topoisomerase II and tubulina. The analysis showed that LDE-etoposide treatment was more effective in treating atherosclerotic-induced lesions in rabbits than the combination between LDE-etoposide/LDE-paclitaxel

Thesis (Ph. D.)--West Virginia University, 2006. / Title from document title page. Document formatted into pages; contains x, 180 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.

No description available.

Thesis (Ph. D.)--Colorado State University, 2004. / Includes bibliographical references.

This thesis aims to develop a new and inexpensive synthetic route to the anti-cancer drug etoposide (6) via 4'-demethylpodophyllotoxin (4) or 4'-demethylepipodophyllotoxin (5) involving the oxidative coupling of a dibenzylbutanolide catalyzed by a cell-free extract (CFE) from plant cell culture. This step was studied in depth using the Catharanthus roseus CFE-catalyzed biotransformation of frans-2-(3,5-dimethoxy-4-hydroxybenzyl)-3-(3-hydroxy-4-methoxybenzyl)butanolide (58) to 1-(3,5-dimethoxy-4-hydroxyphenyl)-6-hydroxy-3-hydroxymethyl-7-methoxy-1,2,3,4-tetrahydro-2-naphthoic acid γ lactone (59) as a model. The optimum values of reaction pH, enzyme:substrate ratio and co-factonsubstrate ratio were determined. The butanolide 58 was synthesized by a route involving the Stobbe condensation of 3-benzyloxy-4-methoxybenzaldehyde with dimethylsuccinate to yield 2-(3-benzyloxy-4-methoxybenzylidene)butanedioic acid 1-methyl ester (69). Hydrogenation of 69 to 2-(3-benzyloxy-4-methoxybenzyl)butanedioic acid 1-methyl ester (70) followed by reductive lactonization afforded 3-(3-benzytoxy-4-methoxybenzyl)butanolide (71). Alkylation of 71 with 4-benzyloxy-a-bromo-3,5-dimethoxytoluene (72) gave frans-2-(4-benzyloxy-3,5-dimethoxybenzyl)-3-(3-benzyloxy-4-methoxybenzyl)butanolide (73) which was then converted to the butanolide 58 by catalytic hydrogenolysis. In order to investigate the effect of different aromatic substituents on the oxidative coupling of butanolides, C. roseus CFE-catalyzed biotransformations of frans-2-(3,5-dimethoxy-4-hydroxybenzyl)-3-(3,4-methylenedioxybenzyl)butanolide (74) and frans-2-(3,5-dimethoxy-4-hydroxybenzyl)-3-(3,4-dihydroxy-a-hydroxybenzyl)butanolide (94) were also performed. The biotransformation of 74 gave 2-(3,5-dimethoxy-4-hydroxybenzylidene)-3-(3,4-methylenedioxybenzyl)butanoiide (76) as the sole isolated product. A pathway involving oxidative demethylatton is proposed to account for the balance of the unrecovered material. The butanolide 94, a potential precursor to etoposide, was prepared from piperonal. The lithium anion of 1-bis(phenylthio)methyl-3,4-methylenedioxybenzene (97) and the bromide 72 were added consecutively to but-2-en-4-olide to afford frans-2-(4-benzyloxy-3,5-dimethoxybenzyl)-3-(3,4-methylenedioxy-α,α-bis(phenylthio)benzyl)butanolide (96). A synthetic sequence involving the oxidation of 96 to frans-2-(4-benzyloxy-3,5-dimethoxybenzyl)-3-(3,4-methylenedioxybenzoyl)-butanolide (100), reduction to frans-2-(4-benzyloxy-3,5-dimethoxybenzyl)-3-(α-hydroxy-3,4-methylenedioxybenzyl)butanolide (109) and cleavage of the methylenedioxy and benzyl protecting groups gave the catechol 94. Unfortunately, the CFE-catalyzed oxidation of 94, following treatment with sodium borohydride, yielded 4-(3,4-dihydroxyphenyl)-5,7-dimethoxy-6-hydroxy-2-hydroxymethyl-1,2,3,4-tetrahydro-2-naphthoic acid γ lactone (103) as the sole isolated product. [Formulas omitted] / Science, Faculty of / Chemistry, Department of / Graduate

No description available.

Four cases of extremity cancers received effective management with cisplatin and etoposide via isolated limb perfusion. They demonstrated minimal, if any, soft tissue damage. This result counters the theory that a caustic response is a prerequisite for successful therapy. This characteristic allows for simultaneous surgical resection with regional, isolated limb perfusion of potent cytotoxic agents without increased morbidity from tissue necrosis, a common consequence of previously used drugs. There is no apparent affect on wound healing, even in cases involving extensive, radical operative procedures.